The present invention relates to a pharmaceutical composition and a method for preventing non-intentional problem behaviors, such as a stereotyped behavior, behaviors caused by separation anxiety, behaviors caused by OCD (obsessive-compulsive disorder). Particularly, the present invention relates to a pharmaceutical composition and a method of preventing excessive barking of companion animals.
In companion animals, problem behaviors, for example, excessive barking of dogs or scratching behaviors to damage skin, has been a controversial problem from various point of view. However, it has not been clearly elucidated why such behaviors occur, for example, why dogs bark. Generally, barking is a normal and natural communication mean for dogs, and it is known that the native causes of barking of dogs are, for example, internal requirements to solve struggles such as the requirement to prevent intruders to their territories, instinctive desires, and appearance of anxiety or struggle. However, the cause of barking is not specified in many cases, and there are many cases where it should be admitted that they are barking non-intentionally.
As a solution for this, methods have generally been adopted where excessive barking is prevented by training. Such methods include methods of punishment by, for example, a water pistol or a can with pebbles or ultrasonic beam. There are also approaches by hitting dogs or shouting at dogs, which may enhance undesired behaviors of dogs and which would be unsuccessful. On the other hand, it is also contrive to control the excessive barking or stereotyped behaviors of companion animals by using special devices. As an examples, the product, AboistopR (Dynavet, France) are referred to as an efficient device in that dogs would seek the location of citronellal order released from the device and, as a result, dogs may be distracted. However, this device is not necessarily effective in some cases such as the case where the dogs are barking from anxiety (for example, in the case of separation anxiety disorder). Furthermore, a training to acclimatize the dog to this device before using AboistopR, or a labor to provide a toy, a person to stay with the dog while your are not at home or a partner dog is also required.
Additionally, a collar which automatically triggers an electrical shock to is widely sold except in England. This collar inflicts a shock circuit through a microphone if the dog barks. The use of this device is not desirable, because the device is recognized as atrocious and is unsuccessful in many cases and also because there is a possibility of significantly injuring the comfort level of dogs.
Furthermore, some veterinarians prescribe Clomipramine or monoamine oxidase inhibitors as a drug having an anxiolytic effect, but these are not effective in many cases. For example Clomipramine is believed to have reduced effectiveness in the case of excessive barking. Monoamine oxidase inhibitors are originally the drugs used for treatment of depression in human, of which efficacy are not confirmed in companion animals and also should not be use in symptomatic treatment.
Finally, the process where the vocal cord is excised may be recommended, but this is like a final process and is not desirable. Actually, most veterinarians in Europe do not accept this process.
On the other hand, independent of the foregoing clinical investigations, many attempts have been made focused on the running activity, especially on the night running activity, during the studies of neuron. For example, the inventors of the present invention reported that when the ventromedial nucleus of hypothalamus (hereinafter simply referred to as “VMH”) of rat was stimulated by water absorbent polymers, the running activity on rat was induced by the pressure stimulus (Yokawa, et. al., Physiology & behavior (1989), 46, 713-717). According to this report, signals from VMH were indicated to be required for the induction of running activity in rat, based on the observation that the running activity did not occur when VMH region had been excised from the animals. Additionally, the inventors demonstrated that the foregoing induction of rat running activity caused by polymers could be inhibited by administration of GABA (γ-aminobutyric acid) (Yokawa, et. al., Physiol. & Behav. (1990), 47, 1261-1264).
The inventors also reported that the running activity in rat might be induced by a kind of ionotropic glutamate receptor, kainate receptor agonists (Narita, et. al., Brain Res. (1993), 603, 243-247). According to the report, the running activity in rat was induced by kainate and was not inhibited by GABA but the running activity was inhibited by DNQX (6,7-dinitroquinoxaline-2,3-dione), a kainate receptor antagonist, which suggest that the neuron controlling the running activity in rat may be stimulated through kainate receptors and that GABAA receptors presynaptically inhibit the neuron controlling the running activity in rat against the kainate receptors. On the other hand, for GABAB receptors, it has been also reported that substances having the competitive inhibitory activity against GABAB receptors are likewise useful in treatment of neurological disease accompanied by convulsion, Alzheimer's disease or memory retention disorder (Japanese unexamined publication, JP 4-243853).